Crystallization and Transformation of Acetaminophen Trihydrate Peterson,*,†
McIlroy,‡
Matthew L. David Mark Oliveira,† and O ¨ rn Almarsson†
Paul
Shaw,†
J. Peter
Mustonen,†
CRYSTAL GROWTH & DESIGN 2003 VOL. 3, NO. 5 761-765
TransForm Pharmaceuticals, Inc., 29 Hartwell Avenue, Lexington, Massachusetts 02421 and Department of Materials Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Received April 11, 2003;
Revised Manuscript Received July 3, 2003
ABSTRACT: Acetaminophen is both polymorphic and prone to the formation of a trihydrate. The recently discovered trihydrate is a lath-like crystalline form that is highly metastable with respect to conversion to the thermodynamically stable form I polymorph. While the trihydrate is physically stable in ice-cold aqueous suspension (with up to 50% propylene glycol or glycerol), conversion of trihydrate takes place at temperatures above 5 °C via a solution-mediated transformation pathway to produce form I. On drying, the optically transparent trihydrate laths transform to an opaque, micronized form I. The metastable trihydrate is characterized as a maximally solvated form that appears to defy Ostwald’s rule of stages and thus behaves fundamentally differently from the highly metastable polymorph form III. Introduction Acetaminophen (4-acetamidophenol; paracetamol) is a well-studied pharmaceutical compound that is known to exhibit polymorphism.1,2 Three crystal forms of the pure substance are known; one of those is a metastable bilayer structure, form III, that was characterized by a combination of high-throughput crystallization experiments and refinements of calculated structures from polymorph prediction.3,4 The relative thermodynamic stability of the polymorphs falls in the order of I > II . III, and the interconversion of the forms follows the reverse order.5 Binary phases of acetaminophen have been made in which hydrogen bonding with amine base is exploited to generate chains of the 1:1 adducts, as well as a 2:1 acetaminophen/4,4′-bipyridine cocrystal.6 A hemisolvate with 1,4-dioxane has also been reported.7 Recently, crystalline monohydrate8a and trihydrate8b forms have been described. The procedure to prepare the trihydrate material involved quench-cooling an aqueous solution and capturing the resulting crystals in oil, enabling the single-crystal structures to be determined. Herein we report on the physical stability of the acetaminophen trihydrate and characterize form conversion in aqueous suspensions and on drying of isolated lath crystals. Experimental Section Reagents. Acetaminophen (lot 100K0197) was from SigmaAldrich. All reagents were used as received. Water was purified using a Fluid Solutions RODI system and tested to have 18.3 MΩ resistivity. Ice was prepared using a Scotsman icemaker and crushed to desired size. Instrumentation. Powder X-ray diffraction experiments were carried out using a Rigaku Rapid-DMAX microdiffractometer. Raman spectra were recorded using a ThermoNicolet Almega Dispersive Raman spectrometer equipped with a 785 nm laser. Differential scanning calorimetric studies were run * Corresponding author. E-mail:
[email protected]. † TransForm Pharmaceuticals. ‡ Massachusetts Institute of Technology.
using a TA Instruments DSC Q1000. Optical microscopy was performed using a Zeiss Axioplan polarized light microscope equipped with a digital camera. Procedures. All crystallization experiments were carried out in 20 mL glass vials fitted with Teflon-sealed metal crimp caps. The vials were arrayed in aluminum blocks that were placed on temperature-controlled aluminum plates. Solutions of acetaminophen in water (20-40 mg/mL) were prepared by heating mixtures to 70 °C for about 30 min.8 Dissolution was monitored visually. After all of the solid acetaminophen had dissolved, the warm solutions (∼10 mL) were filtered into 20 mL glass vials that had been incubated at 60 °C, through 0.2 µm PVDV syringe filters using 10 mL plastic disposable syringe bodies. The glass vials were immediately sealed and transferred to aluminum blocks that had been preheated to 60 °C. After all of the samples had been prepared and arrayed in aluminum blocks, the blocks were cooled to 0 °C over 12 h and then maintained at 0 °C until analyzed. In several samples, laths were observed and subsequently characterized as acetaminophen trihydrate. For seeding experiments, 30 µL of a suspension of acetaminophen trihydrate crystals, prepared by cooling a 30 mg/mL aqueous solution, was added to cooled solutions followed by gentle manual agitation. The concentration of acetaminophen in solution in samples containing trihydrate and form I were measured by HPLC using a UV detector (λ ) 244 nm). Samples used for HPLC analysis were prepared by carefully removing 500 µL of solution from above the crystals and diluting immediately to 250 mL with water in a volumetric flask. Samples were analyzed using a Thermo Hypersil-Keystone Betabasic C18 column on a Waters Alliance System HPLC and 82:15:3 (v/v/v) water/methanol/acetic acid as the mobile phase.
Results and Discussion Crystallization of the Trihydrate by Cooling. Out of 40 crystallization attempts, five samples spontaneously produced the trihydrate. Other samples produced the monoclinic form I crystals from supersaturated solution within a week, but some samples did not spontaneously nucleate after more than one week. Samples that contained a nominal concentration of greater than 35 mg/mL acetaminophen generated form I acetaminophen, based on PXRD. Rapid cooling in a -20 °C freezer caused nucleation and growth of form I
10.1021/cg0340603 CCC: $25.00 © 2003 American Chemical Society Published on Web 07/31/2003
762
Crystal Growth & Design, Vol. 3, No. 5, 2003
Peterson et al.
Figure 1. Powder X-ray diffractograms for form I (I), form II (II), the trihydrate (T), and a mixture of form I and the trihydrate (I + T).
crystals. Furthermore, highly supersaturated solutions (40 mg/mL and above) generate only form I at 0 °C, but readily grow the trihydrate if seeded with trihydrate laths. Crystallization of the Trihydrate by Seeding of Saturated Aqueous Solutions. Form I acetaminophen was dissolved in water by warming to 60-65 °C. Upon rapid cooling of the sample to 0 °C and subsequent seeding with
